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Clinical Correlates of Infliximab (IFX) Failure in Pediatric Patients With Inflammatory Bowel Disease (IBD): A Single Center Experience of Patient Characteristics, Concomitant Medical Therapy and Outcomes
age of diagnosis, disease duration prior to IFX and medication hx. Outcome measures: HBI, hospitalization, surgery, transfusions and cessation of corticosteroids (cs). Log-rank tests and Cox regression were used for clinical correlates of IF; paired t-tests and McNemar's test were used for changes with rescue meds. P-values of <0.05 were statistically significant (SS). Results: Study group: 133 pts. (103 Crohn dis (CD), 24 UC, 6 indeterm. colitis (IC)), mean age at dx 11.7 ±3.2 yrs (3-17yrs), IF (n=61) and IR (n=72). Median # of infusions to loss of response (LOR) was 20; Median time to LOR (TTL) was 36 mos. Factors assoc. with IF: younger age at dx (Hazard Ratio (HR) = 1.11, p= 0.01), disease duration prior to IFX (HR = 1.01, p <0.01), failure of response to 6MP/AZA (median TTL 31 mos. v. not yet reached, p= 0.03) and MTX (median TTL 11 mos. v. 85 mos., p <0.01), and surgery prior to IFX (median TTL 13 mos. v. 49 mos., p <0.01). The following did not reach SS: IBD type (UC v CD, p= 0.12), disease location and behavior for CD (inflam p= 0.39, strict p= 0.97, penetrating p= 0.72), cs hx (p= 0.46), IBD serology (p=0.14-0.98), baseline HBI (9.5 v 9.7, p= 0.89), hospitalization (p= 0.17) or transfusion (p= 0.67). Concomitant rx at LOR: MTX (23%), 6MP/AZA (49%). HACA positivity in IF: 28/44 pts. (64%); 17/ 23 pts (74%) with concomitant 6MP/AZA at time of LOR were HACA positive v. 11/21 (52%) without concomitant 6MP/AZA (p=0.21), HACA positivity with MTX 4/9 (44%) v. 24/35 (69%) without MTX (p=0.25). Rescue rx: adalimumab alone or with 6MP/AZA or MTX, 6MP/AZA or MTX alone, thalidomide and tacrolimus. Conclusions: Pediatric pts with LOR to IFX, were younger at diagnosis of IBD with longer duration of disease and had higher rates failure to respond to 6MP/AZA and MTX and surgery than pts who responded to IFX. IBD type (CD v UC), location and behavior of CD and IBD serology did not affect response to IFX. Rescue therapy, primarily adalimumab, resulted in normalization of HBI and cessation of cs in 66% of IFX failure pts. Outcomes of Pediatric Patients with IFX Failure Before and After Rescue Therapy
Su1910 Identification of Inflammatory Bowel Disease (IBD)-Specific Diagnostic Biomarkers Using Transcriptional Profiling of Peripheral Blood Mononuclear Cells (PBMC) From Treatment NaïVE Children With Either IBD or Non-IBD Gastrointestinal Inflammatory Disorders Alessio Morley-Fletcher, Manoj Bhasin, Ramakrishna C. Konaparthi, Marie G. Joseph, Lauren Henderson, Dongxu Lin, Harland S. Winter, Towia A. Libermann
*Numbers in table are mean (SD).P-values are from paired t-tests Numbers in table are % rate. P-values are from McNemar's test Su1912
Background: While various genetic predisposition markers for inflammatory bowel disease (IBD), have been identified, most previous attempts to identify genomic determinants of IBD have been performed in adults with IBD, or patients with established IBD who are on treatment, and compared to healthy controls. We now report an IBD-specific diagnostic gene signature from peripheral blood mononuclear cells (PBMC) obtained from treatmentnaïve children with gastrointestinal inflammatory disorders that accurately distinguishes children subsequently diagnosed with IBD from children with non-IBD inflammatory diseases. Methods: After obtaining informed consent/assent, we assessed the peripheral blood gene expression profile of 8 IBD and 5 non-IBD subjects using the HT U133+ PM arrayplate (Affymetrix). After normalization using the robust multi-chip analysis (RMA) algorithm, differentially expressed genes were identified using non-parametric (RankProd) methods. To understand the underlying biological mechanisms associated with IBD genes, we performed functional categories, canonical pathways, and interactive network based analysis. An IBDspecific predictor was generated using weighted-voting algorithm and validated using leaveone-out-cross validation on this training set. We further validated our predictor on an independent, previously published dataset (GSE3365) that compares PBMC transcriptional profiles of adult patients with IBD to healthy controls. Results: Unsupervised analysis using principal component analysis separated IBD patients from controls. Supervised analysis identified 456 differentially expressed transcripts with FDR <0.05 between IBD and nonIBD gastrointestinal inflammatory disorders. These IBD-specific genes are significantly enriched for gene ontology categories (P value <0.05) related to immune and inflammatory response, antigen processing and presentation, autoimmune disease as well as NK cell mediated cytotoxicity and participate in T cell, NK cell, neutrophil, macrophage and dendritic cell activities. A 10-gene predictor was able to achieve an accuracy of 92% for diagnosing IBD in the training set. The performance of the biomarkers was validated on a published dataset consisting of 42 healthy individuals and 85 adult IBD patients achieving an accuracy of 71% (sensitivity=70 %, specificity=76%). Conclusion: PBMCs from treatment-naïve pediatric IBD patients express a unique set of genes that clearly segregates IBD from other inflammatory GI disorders and indicates distinct immunological differences specific for IBD. Our results also demonstrate that peripheral blood may emerge as a valuable source for clinically relevant biomarkers. This work was supported by a grant from The Pediatric IBD Foundation and the Harvard Catalyst.
The Developmental Milestone of Autonomy is Delayed When Inflammatory Bowel Disease is Diagnosed Before the Age of 18 Karen I. Kroeker, Jonathan Wong, Richard N. Fedorak BACKGROUND: Children with chronic illnesses diagnosed in childhood often achieve fewer milestones, or at a later age, than healthy children. Interestingly, the diagnosis of inflammatory bowel disease (IBD) earlier in childhood (age 8 to 11 yrs) appears to impact milestones to a lesser degree than if the diagnosis was made in adolescence. AIM: To determine at what age in childhood the diagnosis of IBD maximally impacts developmental milestones and which unique milestones are most affected. METHODS: IBD patients (18-30y) were identified using a University-based gastroenterology patient care database and recruited in clinic, by mail, and by telephone. Interested participants were consented and provided questionnaires to complete and return by mail. The questionnaires determined demographics and the previously validated Course of Life Questionnaire was used to assess timing of milestones in domains of autonomy, psychosexual development, social development, anti-social behavior, and substance use and gambling. The maximal score in each domain is listed in the table below; the higher the score the closer to “normal”. RESULTS: 203 patients with IBD completed the questionnaires. 60.6% were female and 63.5% had a diagnosis of Crohn's disease. Table 1 demonstrates the combined IBD Course of Life scores by age of diagnosis (Dx) and milestone domain. Results for Dx<12 and Dx12-17 were compared to Dx18-30. The diagnosis of IBD before age 12 and between age 12 and 17 negatively impacts the developmental milestone of autonomy but does not affect the other core milestones. Univariate analysis demonstrated that those most affected by an IBD diagnosis during childhood are males and those diagnosed with Crohn's disease. CONCLUSION: A diagnosis of IBD before the age of 18 years negatively impacts the developmental milestone of autonomy, whereas the other milestones of psychosexual, social development, anti-social behavior and substance use and gambling are not affected. This study identifies young male patients and those with a diagnosis of Crohn's as most vulnerable for poor autonomy development. Table 1. Course of Life Scores by Age of Diagnosis
Su1911 Clinical Correlates of Infliximab (IFX) Failure in Pediatric Patients With Inflammatory Bowel Disease (IBD): A Single Center Experience of Patient Characteristics, Concomitant Medical Therapy and Outcomes Lina M. Felipez, Ranjana Gokhale, Kristen Wroblewski, Anna Godick, Barbara S. Kirschner Background: IBD is a chronic relapsing condition requiring treatment to induce and maintain remission. IFX, an anti TNF-α, has proven efficiency with response rates to 88.4% in pediatric patients (ped pts) with mod-sev. IBD. Aim: To report our experience in ped pts with IBD and assess factors that might predict IFX failure. Treatment regimens and outcomes after IFX failure were also evaluated. Methods: A computerized database at the Univ. of Chicago was used to identify children with IBD who received IFX. Medical records were analyzed for IFX failure (IF) or IFX response (IR) based on Harvey-Bradshaw Index (HBI>7 or <5). Data analyzed: IBD type, location and behavior (inflam, strict, penetrating) for CD,
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AGA Abstracts
AGA Abstracts
METHODS: By retrospective chart review at MGHfC between January 2003 and September 2010, we identified pediatric patients who had pelvic MRI for perianal fistula prior to starting anti-TNF alpha therapy. RESULTS: We identified 15 patients (11 male; mean age 14 years; range 8-19 years) who had an MRI identifying a perianal fistula and subsequently received infliximab (5-10mg/kg). Subjects who failed treatment with infliximab or developed an adverse reaction changed to adalimumab or certolizumab. Nine patients had perianal fistulas, 3 had combined perianal/peritoneal fistulas, 1 had a recto-vaginal and 2 had recto-scrotal fistulas. 10 of the 15 patients had multiple fistulas on presentation and 11 had associated fluid collections seen on MRI. Based on the Parks criteria, there were 9 intersphincteric fistulas, 12 transphincteric, and 3 suprasphincteric. Six of 15 patients (40 percent) with perianal fistulas had a complete clinical response (mean duration to resolution 29.3 months); 1 of these 6 patients relapsed after infliximab was discontinued and did not respond to retreatment (6 months). Two patients (13 percent) had a partial clinical response to antiTNF therapy and 7 patients (47 percent) had minimal response with continued drainage. Seton drainage and/or fistulectomy were used prior to medical treatment in a total of 6 patients, 2 of whom had a complete response. Of the 6 patients with complete clinical response, 1 had a recto-vaginal fistula, and 1 had a recto-scrotal fistula. Repeat MRI evaluation was performed on 4 of the 6 patients with complete clinical response, showing complete radiologic healing in 3 patients and persistence of fistula with active inflammation in 1 patient. Both of the patients with partial response had MRI:one showed worsening of the fistula tract and the other was improved. Three of the 7 patients with minimal response to anti-TNF therapy had repeat imaging and all demonstrated persistence of active fistulous tracts. Two of these patients eventually required diversion procedures. CONCLUSIONS: TNF alpha antagonist therapy resulted in complete healing in 40 percent of pediatric and adolescent Crohn's patients with perianal fistulas and partial healing in 13 percent. Mean time to complete clinical response was longer than expected - almost 30 months. Clinical response to treatment correlated with radiologic evaluation in 7 of 9 patients who underwent repeat imaging. Based on Parks criteria, the complexity of the fistula did not appear to influence the response to treatment. Supported in part by a grant from The Pediatric IBD Foundation
Su1910 Identification of Inflammatory Bowel Disease (IBD)-Specific Diagnostic Biomarkers Using Transcriptional Profiling of Peripheral Blood Mononuclear Cells (PBMC) From Treatment NaïVE Children With Either IBD or Non-IBD Gastrointestinal Inflammatory Disorders Alessio Morley-Fletcher, Manoj Bhasin, Ramakrishna C. Konaparthi, Marie G. Joseph, Lauren Henderson, Dongxu Lin, Harland S. Winter, Towia A. Libermann
*Numbers in table are mean (SD).P-values are from paired t-tests Numbers in table are % rate. P-values are from McNemar's test Su1912
Background: While various genetic predisposition markers for inflammatory bowel disease (IBD), have been identified, most previous attempts to identify genomic determinants of IBD have been performed in adults with IBD, or patients with established IBD who are on treatment, and compared to healthy controls. We now report an IBD-specific diagnostic gene signature from peripheral blood mononuclear cells (PBMC) obtained from treatmentnaïve children with gastrointestinal inflammatory disorders that accurately distinguishes children subsequently diagnosed with IBD from children with non-IBD inflammatory diseases. Methods: After obtaining informed consent/assent, we assessed the peripheral blood gene expression profile of 8 IBD and 5 non-IBD subjects using the HT U133+ PM arrayplate (Affymetrix). After normalization using the robust multi-chip analysis (RMA) algorithm, differentially expressed genes were identified using non-parametric (RankProd) methods. To understand the underlying biological mechanisms associated with IBD genes, we performed functional categories, canonical pathways, and interactive network based analysis. An IBDspecific predictor was generated using weighted-voting algorithm and validated using leaveone-out-cross validation on this training set. We further validated our predictor on an independent, previously published dataset (GSE3365) that compares PBMC transcriptional profiles of adult patients with IBD to healthy controls. Results: Unsupervised analysis using principal component analysis separated IBD patients from controls. Supervised analysis identified 456 differentially expressed transcripts with FDR <0.05 between IBD and nonIBD gastrointestinal inflammatory disorders. These IBD-specific genes are significantly enriched for gene ontology categories (P value <0.05) related to immune and inflammatory response, antigen processing and presentation, autoimmune disease as well as NK cell mediated cytotoxicity and participate in T cell, NK cell, neutrophil, macrophage and dendritic cell activities. A 10-gene predictor was able to achieve an accuracy of 92% for diagnosing IBD in the training set. The performance of the biomarkers was validated on a published dataset consisting of 42 healthy individuals and 85 adult IBD patients achieving an accuracy of 71% (sensitivity=70 %, specificity=76%). Conclusion: PBMCs from treatment-naïve pediatric IBD patients express a unique set of genes that clearly segregates IBD from other inflammatory GI disorders and indicates distinct immunological differences specific for IBD. Our results also demonstrate that peripheral blood may emerge as a valuable source for clinically relevant biomarkers. This work was supported by a grant from The Pediatric IBD Foundation and the Harvard Catalyst.
The Developmental Milestone of Autonomy is Delayed When Inflammatory Bowel Disease is Diagnosed Before the Age of 18 Karen I. Kroeker, Jonathan Wong, Richard N. Fedorak BACKGROUND: Children with chronic illnesses diagnosed in childhood often achieve fewer milestones, or at a later age, than healthy children. Interestingly, the diagnosis of inflammatory bowel disease (IBD) earlier in childhood (age 8 to 11 yrs) appears to impact milestones to a lesser degree than if the diagnosis was made in adolescence. AIM: To determine at what age in childhood the diagnosis of IBD maximally impacts developmental milestones and which unique milestones are most affected. METHODS: IBD patients (18-30y) were identified using a University-based gastroenterology patient care database and recruited in clinic, by mail, and by telephone. Interested participants were consented and provided questionnaires to complete and return by mail. The questionnaires determined demographics and the previously validated Course of Life Questionnaire was used to assess timing of milestones in domains of autonomy, psychosexual development, social development, anti-social behavior, and substance use and gambling. The maximal score in each domain is listed in the table below; the higher the score the closer to “normal”. RESULTS: 203 patients with IBD completed the questionnaires. 60.6% were female and 63.5% had a diagnosis of Crohn's disease. Table 1 demonstrates the combined IBD Course of Life scores by age of diagnosis (Dx) and milestone domain. Results for Dx<12 and Dx12-17 were compared to Dx18-30. The diagnosis of IBD before age 12 and between age 12 and 17 negatively impacts the developmental milestone of autonomy but does not affect the other core milestones. Univariate analysis demonstrated that those most affected by an IBD diagnosis during childhood are males and those diagnosed with Crohn's disease. CONCLUSION: A diagnosis of IBD before the age of 18 years negatively impacts the developmental milestone of autonomy, whereas the other milestones of psychosexual, social development, anti-social behavior and substance use and gambling are not affected. This study identifies young male patients and those with a diagnosis of Crohn's as most vulnerable for poor autonomy development. Table 1. Course of Life Scores by Age of Diagnosis
Su1911 Clinical Correlates of Infliximab (IFX) Failure in Pediatric Patients With Inflammatory Bowel Disease (IBD): A Single Center Experience of Patient Characteristics, Concomitant Medical Therapy and Outcomes Lina M. Felipez, Ranjana Gokhale, Kristen Wroblewski, Anna Godick, Barbara S. Kirschner Background: IBD is a chronic relapsing condition requiring treatment to induce and maintain remission. IFX, an anti TNF-α, has proven efficiency with response rates to 88.4% in pediatric patients (ped pts) with mod-sev. IBD. Aim: To report our experience in ped pts with IBD and assess factors that might predict IFX failure. Treatment regimens and outcomes after IFX failure were also evaluated. Methods: A computerized database at the Univ. of Chicago was used to identify children with IBD who received IFX. Medical records were analyzed for IFX failure (IF) or IFX response (IR) based on Harvey-Bradshaw Index (HBI>7 or <5). Data analyzed: IBD type, location and behavior (inflam, strict, penetrating) for CD,
S-509
AGA Abstracts
AGA Abstracts
METHODS: By retrospective chart review at MGHfC between January 2003 and September 2010, we identified pediatric patients who had pelvic MRI for perianal fistula prior to starting anti-TNF alpha therapy. RESULTS: We identified 15 patients (11 male; mean age 14 years; range 8-19 years) who had an MRI identifying a perianal fistula and subsequently received infliximab (5-10mg/kg). Subjects who failed treatment with infliximab or developed an adverse reaction changed to adalimumab or certolizumab. Nine patients had perianal fistulas, 3 had combined perianal/peritoneal fistulas, 1 had a recto-vaginal and 2 had recto-scrotal fistulas. 10 of the 15 patients had multiple fistulas on presentation and 11 had associated fluid collections seen on MRI. Based on the Parks criteria, there were 9 intersphincteric fistulas, 12 transphincteric, and 3 suprasphincteric. Six of 15 patients (40 percent) with perianal fistulas had a complete clinical response (mean duration to resolution 29.3 months); 1 of these 6 patients relapsed after infliximab was discontinued and did not respond to retreatment (6 months). Two patients (13 percent) had a partial clinical response to antiTNF therapy and 7 patients (47 percent) had minimal response with continued drainage. Seton drainage and/or fistulectomy were used prior to medical treatment in a total of 6 patients, 2 of whom had a complete response. Of the 6 patients with complete clinical response, 1 had a recto-vaginal fistula, and 1 had a recto-scrotal fistula. Repeat MRI evaluation was performed on 4 of the 6 patients with complete clinical response, showing complete radiologic healing in 3 patients and persistence of fistula with active inflammation in 1 patient. Both of the patients with partial response had MRI:one showed worsening of the fistula tract and the other was improved. Three of the 7 patients with minimal response to anti-TNF therapy had repeat imaging and all demonstrated persistence of active fistulous tracts. Two of these patients eventually required diversion procedures. CONCLUSIONS: TNF alpha antagonist therapy resulted in complete healing in 40 percent of pediatric and adolescent Crohn's patients with perianal fistulas and partial healing in 13 percent. Mean time to complete clinical response was longer than expected - almost 30 months. Clinical response to treatment correlated with radiologic evaluation in 7 of 9 patients who underwent repeat imaging. Based on Parks criteria, the complexity of the fistula did not appear to influence the response to treatment. Supported in part by a grant from The Pediatric IBD Foundation